Disorders of gonadal and phenotypic sex can result in underandrogenization of individuals with a 46,XY karyotype (46,XY DSD) and the excess androgenization of individuals with a 46,XX karyotype (46,XX DSD) (Table 10-1). These disorders cover a spectrum of phenotypes ranging from “46,XY phenotypic females” or “46,XX phenotypic males” to individuals with atypical genitalia.
Underandrogenization of the 46,XY fetus (formerly called male pseudohermaphroditism) reflects defects in androgen production or action. It can result from disorders of testis development, defects of androgen synthesis, or resistance to testosterone and DHT (Table 10-1).
Disorders of testis development
Pure (or complete) gonadal dysgenesis (Swyer’s syndrome) is associated with streak gonads, müllerian structures (due to insufficient AMH/MIS secretion), and a complete absence of androgenization. Phenotypic females with this condition often present because of absent pubertal development and are found to have a 46,XY karyotype. Serum sex steroids, AMH/MIS, and inhibin B are low, and LH and FSH are elevated. Patients with partial gonadal dysgenesis (dysgenetic testes) may produce enough MIS to regress the uterus and sufficient testosterone for partial androgenization, and therefore usually present in the newborn period with atypical genitalia. Gonadal dysgenesis can result from mutations or deletions of testis-promoting genes (WT1, CBX2, SF1, SRY, SOX9, MAP3K1, DHH, GATA4, ATRX, ARX, DMRT) or duplication of chromosomal loci containing “antitestis” genes (e.g., WNT4/RSPO1, DAX1) (Table 10-3). Among these, deletions or mutations of SRY and heterozygous mutations of SF1 (NR5A1) appear to be most common but still account collectively for <25% of cases. Associated clinical features may be present, reflecting additional functional roles for these genes. For example, renal dysfunction occurs in patients with specific WT1 mutations (Denys-Drash and Frasier’s syndromes), primary adrenal failure occurs in some patients with SF1 mutations, and severe cartilage abnormalities (campomelic dysplasia) are the predominant clinical feature of SOX9 mutations. A family history of DSD, infertility, or early menopause is important because mutations in SF1/NR5A1 can be inherited from a mother in a sex-limited dominant manner (which can mimic X-linked inheritance). In some cases, a woman may later develop primary ovarian insufficiency because of the effect of SF1 on the ovary. Intraabdominal dysgenetic testes should be removed to prevent malignancy, and estrogens can be used to induce secondary sex characteristics and uterine development in 46,XY individuals raised as females, if it is felt that a female gender identity is established. Absent (vanishing) testis syndrome (bilateral anorchia) reflects regression of the testis during development. The etiology is unknown, but the absence of müllerian structures indicates adequate secretion of AMH early in utero. In most cases, androgenization of the external genitalia is either normal or slightly impaired (e.g., small penis, hypospadias). These individuals can be offered testicular prostheses and should receive androgen replacement in adolescence.
TABLE 10-3Selected Genetic Causes of 46,XY Disorders of Sex Development (DSDs) ||Download (.pdf) TABLE 10-3 Selected Genetic Causes of 46,XY Disorders of Sex Development (DSDs)
|GENE ||INHERITANCE ||GONAD ||UTERUS ||EXTERNAL GENITALIA ||ASSOCIATED FEATURES |
|Disorders of Testis Development |
|WT1 ||AD ||Dysgenetic testis ||+/− ||Female or ambiguous ||Wilms’ tumor, renal abnormalities, gonadal tumors (WAGR, Denys-Drash and Frasier’s syndromes) |
|CBX2 ||AD ||Ovary ||+ ||Female || |
|SF1 ||AR/AD (SL) ||Dysgenetic testis/Leydig dysfunction ||+/− ||Female or ambiguous ||Primary adrenal failure; primary ovarian insufficiency in female (46,XX) relatives |
|SRY ||Y ||Dysgenetic testis or ovotestis ||+/− ||Female or ambiguous || |
|SOX9 ||AD ||Dysgenetic testis or ovotestis ||+/− ||Female or ambiguous ||Campomelic dysplasia |
|MAP3K1 ||AD (SL) ||Dysgenetic testis ||+/− ||Female or ambiguous || |
|DHH ||AR ||Dysgenetic testis ||+ ||Female ||Minifascicular neuropathy |
|GATA4 ||AD ||Dysgenetic testis ||− ||Ambiguous or male ||Congenital heart disease |
|ATRX ||X ||Dysgenetic testis ||− ||Female or ambiguous ||α Thalassemia, developmental delay |
|ARX ||X ||Dysgenetic testis ||− ||Male or ambiguous ||Developmental delay; X-linked lissencephaly |
|MAMLD1 ||X ||Dysgenetic testis/Leydig dysfunction ||− ||Hypospadias || |
|DAX1 ||dupXp21 ||Dysgenetic testis ||+/− ||Female or ambiguous || |
|WNT4/RSPO1 ||dup1p35 ||Dysgenetic testis ||+ ||Ambiguous || |
|Disorders of Androgen Synthesis |
|LHR ||AR ||Testis ||− ||Female, ambiguous or micropenis ||Leydig cell hypoplasia |
|DHCR7 ||AR ||Testis ||− ||Variable ||Smith-Lemli-Opitz syndrome: coarse facies, second-third toe syndactyly, failure to thrive, developmental delay, cardiac and visceral abnormalities |
|StAR ||AR ||Testis ||− ||Female or ambiguous ||Congenital lipoid adrenal hyperplasia (primary adrenal failure) |
|CYP11A1 ||AR ||Testis ||− ||Ambiguous ||Primary adrenal failure |
|HSD3B2 ||AR ||Testis ||− ||Ambiguous ||CAH, primary adrenal failure ± salt loss, partial androgenization due to ↑ DHEA |
|CYP17 ||AR ||Testis ||− ||Female or ambiguous ||CAH, hypertension due to ↑ corticosterone and 11-deoxycorticosterone, except in isolated 17,20-lyase deficiency |
|CYB5A ||AR ||Testis ||− ||Ambiguous ||Apparent isolated 17,20-lyase deficiency; methemoglobinemia |
|POR ||AR ||Testis ||− ||Ambiguous or male ||Mixed features of 21-hydroxylase deficiency and 17α-hydroxylase/17,20-lyase deficiency, sometimes associated with Antley-Bixler craniosynostosis |
|Disorders of Androgen Synthesis |
|HSD17B3 ||AR ||Testis ||− ||Female or ambiguous ||Partial androgenization at puberty, ↑ androstenedione-to-testosterone ratio |
|SRD5A2 ||AR ||Testis ||− ||Ambiguous or micropenis ||Partial androgenization at puberty, ↑ testosterone-to-dihydrotestosterone ratio |
|AKR1C2 (AKR1C4) ||AR ||Testis ||− ||Female or ambiguous ||Decreased fetal DHT production |
|Disorders of Androgen Action |
|Androgen receptor ||X ||Testis ||− ||Female, ambiguous, micropenis or normal male ||Phenotypic spectrum from complete androgen insensitivity syndrome (female external genitalia) and partial androgen insensitivity (ambiguous) to normal male genitalia and infertility |
Disorders of androgen synthesis
Defects in the pathway that regulates androgen synthesis (Fig. 10-4) cause underandrogenization of the 46,XY fetus (Table 10-1). Müllerian regression is unaffected because Sertoli cell function is preserved. Most of these conditions can present with a spectrum of genital phenotypes, ranging from female-typical external genitalia or clitoromegaly in the more severe situations to penoscrotal hypospadias or a small phallus in others.
Simplified overview of glucocorticoid and androgen synthesis pathways. Defects in CYP21A2 and CYP11B1 shunt steroid precursors into the androgen pathway and cause androgenization of the 46,XX fetus. Testosterone is synthesized in the testicular Leydig cells and converted to dihydrotestosterone peripherally. Defects in enzymes involved in androgen synthesis result in underandrogenization of the 46,XY fetus. StAR, steroidogenic acute regulatory protein. (After E Braunwald et al [eds]: Harrison’s Principles of Internal Medicine, 15th ed. New York, McGraw-Hill, 2001.)
Mutations in the LH receptor (LHCGR) cause Leydig cell hypoplasia and androgen deficiency, due to impaired actions of human chorionic gonadotropin in utero and LH late in gestation and during the neonatal period. As a result, testosterone and DHT synthesis are insufficient for complete androgenization.
Steroidogenic enzyme pathways
Mutations in steroidogenic acute regulatory protein (StAR) and CYP11A1 affect both adrenal and gonadal steroidogenesis (Fig. 10-4) (Chap. 8). Affected individuals (46,XY) usually have severe early-onset salt-losing adrenal failure and a female phenotype, although later-onset milder variants have been reported. Defects in 3β-hydroxysteroid dehydrogenase type 2 (HSD3β2) also cause adrenal insufficiency in severe cases, but the accumulation of dehydroepiandrosterone (DHEA) has a mild androgenizing effect, resulting in ambiguous genitalia or hypospadias. Salt loss occurs in many but not all cases. Patients with CAH due to 17α-hydroxylase (CYP17) deficiency have variable underandrogenization and develop hypertension and hypokalemia due to the potent salt-retaining effects of corticosterone and 11-deoxycorticosterone. Patients with complete loss of 17α-hydroxylase function often present as phenotypic females who fail to enter puberty and are found to have inguinal testes and hypertension in adolescence. Some mutations in CYP17 selectively impair 17,20-lyase activity without altering 17α-hydroxylase activity, leading to underandrogenization without mineralocorticoid excess and hypertension. Disruption of the coenzyme, cytochrome b5 (CYB5A), can present similarly, and methemoglobinemia is usually present. Mutations in P450 oxidoreductase (POR) affect multiple steroidogenic enzymes, leading to impaired androgenization and a biochemical pattern of apparent combined 21-hydroxylase and 17α-hydroxylase deficiency, sometimes with skeletal abnormalities (Antley-Bixler craniosynostosis). Defects in 17β-hydroxysteroid dehydrogenase type 3 (HSD17β3) and 5α-reductase type 2 (SRD5A2) interfere with the synthesis of testosterone and DHT, respectively. These conditions are characterized by minimal or absent androgenization in utero, but some phallic development can occur during adolescence due to the action of other enzyme isoforms. Individuals with 5α-reductase type 2 deficiency have normal wolffian structures and usually do not develop breast tissue. At puberty, the increase in testosterone induces muscle mass and other virilizing features despite DHT deficiency. Some individuals change gender from female to male at puberty. Thus, the management of this disorder is challenging. DHT cream can improve prepubertal phallic growth in patients raised as male. Gonadectomy before adolescence and estrogen replacement at puberty can be considered in individuals raised as females who have a female gender identity. Disruption of alternative pathways to fetal DHT production might also present with 46,XY DSD (AKR1C2/AKR1C4).
Disorders of androgen action
Androgen insensitivity syndrome
Mutations in the androgen receptor cause resistance to androgen (testosterone, DHT) action or the androgen insensitivity syndrome (AIS). AIS is a spectrum of disorders that affects at least 1 in 100,000 46,XY individuals. Because the androgen receptor is X-linked, only 46,XY offspring are affected if the mother is a carrier of a mutation. XY individuals with complete AIS (formerly called testicular feminization syndrome) have a female phenotype, normal breast development (due to aromatization of testosterone), a short vagina but no uterus (because MIS production is normal), scanty pubic and axillary hair, and a female gender identity and sex role behavior. Gonadotropins and testosterone levels can be low, normal, or elevated, depending on the degree of androgen resistance and the contribution of estradiol to feedback inhibition of the hypothalamic-pituitary-gonadal axis. AMH/MIS levels in childhood are normal or high. Most patients present with inguinal hernias (containing testes) in childhood or with primary amenorrhea in late adolescence. Gonadectomy sometimes is offered for girls diagnosed in childhood, because there is a low risk of malignancy, and estrogen replacement is prescribed. Alternatively, the gonads can be left in situ until breast development is complete and removed because of tumor risk. Some adults with complete AIS decline gonadectomy, but should be counseled about the risk of malignancy, especially because early detection of premalignant changes by imaging or biomarkers is currently not possible. The use of graded dilators in adolescence is usually sufficient to dilate the vagina for sexual intercourse.
Partial AIS (Reifenstein’s syndrome) results from androgen receptor mutations that maintain residual function. Patients often present in infancy with penoscrotal hypospadias and small undescended testes and with gynecomastia at the time of puberty. Those individuals raised as males usually require hypospadias repair in childhood and may need breast reduction in adolescence. Some boys enter puberty spontaneously. High-dose testosterone has been given to support development if puberty does not progress, but long-term data are limited. More severely underandrogenized patients present with clitoral enlargement and labial fusion and may be raised as females. The surgical and psychosexual management of these patients is complex and requires active involvement of the parents and the patient during the appropriate stages of development. Azoospermia and male-factor infertility also have been described in association with mild loss-of-function mutations in the androgen receptor.
OTHER DISORDERS AFFECTING 46,XY MALES
Persistent müllerian duct syndrome is the presence of a uterus in an otherwise phenotypic male. This condition can result from mutations in AMH or its receptor (AMHR2). The uterus may be removed, but only if damage to the vasa deferentia and blood supply can be avoided. Isolated hypospadias occurs in ~1 in 250 males and is usually repaired surgically. Most cases are idiopathic, although evidence of penoscrotal hypospadias, poor phallic development, and/or bilateral cryptorchidism requires investigation for an underlying DSD (e.g., partial gonadal dysgenesis, mild defect in testosterone action, or even severe forms of 46,XX CAH). Unilateral undescended testes (cryptorchidism) affect more than 3% of boys at birth. Orchidopexy should be considered if the testis has not descended by 6–9 months of age. Bilateral cryptorchidism occurs less frequently and should raise suspicion of gonadotropin deficiency or DSD. A small subset of patients with cryptorchidism may have mutations in the insulin-like 3 (INSL3) gene or its receptor LGR8 (also known as GREAT), which mediates normal testicular descent. Syndromic associations and intrauterine growth retardation also occur relatively frequently in association with impaired testicular function or target tissue responsiveness, but the underlying etiology of many of these conditions is unknown.
Inappropriate androgenization of the 46,XX fetus (formerly called female pseudohermaphroditism) occurs when the gonad (ovary) contains androgen-secreting testicular material or after increased androgen exposure, which is usually adrenal in origin (Table 10-1).
46,XX testicular/ovotesticular DSD
Testicular tissue can develop in 46,XX testicular DSD (46,XX males) after translocation of SRY, duplication of SOX9, or defects in RSPO1 (Table 10-4).
TABLE 10-4Selected Genetic Causes of 46,XX Disorders of Sex Development (DSDs) ||Download (.pdf) TABLE 10-4 Selected Genetic Causes of 46,XX Disorders of Sex Development (DSDs)
|GENE ||INHERITANCE ||GONAD ||UTERUS ||EXTERNAL GENITALIA ||ASSOCIATED FEATURES |
|Testicular/Ovotesticular DSD |
|SRY ||Translocation ||Testis or ovotestis ||− ||Male or ambiguous || |
|SOX9 ||dup17q24 ||Unknown ||− ||Male or ambiguous || |
|RSPO1 ||AR ||Testis or ovotestis ||± ||Male or ambiguous ||Palmar plantar hyperkeratosis, squamous cell skin carcinoma |
|WNT4 ||AR ||Testis or ovotestis ||− ||Male or ambiguous ||SERKAL syndrome (renal dysgenesis, adrenal and lung hypoplasia) |
|Increased Androgen Synthesis |
|HSD3B2 ||AR ||Ovary ||+ ||Clitoromegaly ||CAH, primary adrenal failure, mild androgenization due to ↑ DHEA |
|CYP21A2 ||AR ||Ovary ||+ ||Ambiguous ||CAH, phenotypic spectrum from severe salt-losing forms associated with adrenal failure to simple virilizing forms with compensated adrenal function, ↑ 17-hydroxyprogesterone |
|POR ||AR ||Ovary ||+ ||Ambiguous or female ||Mixed features of 21-hydroxylase deficiency and 17α-hydroxylase/17,20-lyase deficiency, sometimes associated with Antley-Bixler craniosynostosis |
|CYP11B1 ||AR ||Ovary ||+ ||Ambiguous ||CAH, hypertension due to ↑ 11-deoxycortisol and 11-deoxycorticosterone |
|CYP19 ||AR ||Ovary ||+ ||Ambiguous ||Maternal virilization during pregnancy, absent breast development at puberty |
|Glucocorticoid receptor ||AR ||Ovary ||+ ||Ambiguous ||↑ ACTH, 17-hydroxyprogesterone and cortisol; failure of dexamethasone suppression |
Increased androgen exposure
21-Hydroxylase deficiency (congenital adrenal hyperplasia)
The classic form of 21-hydroxylase deficiency (21-OHD) is the most common cause of CAH (Chap. 8). It has an incidence between 1 in 10,000 and 1 in 15,000 and is the most common cause of androgenization in chromosomal 46,XX females (Table 10-4). Affected individuals are homozygous or compound heterozygous for severe mutations in the enzyme 21-hydroxylase (CYP21A2). This mutation causes a block in adrenal glucocorticoid and mineralocorticoid synthesis, increasing 17-hydroxyprogesterone and shunting steroid precursors into the androgen synthesis pathway (Fig. 10-4). Glucocorticoid insufficiency causes a compensatory elevation of adrenocorticotropin (ACTH), resulting in adrenal hyperplasia and additional synthesis of steroid precursors proximal to the enzymatic block. Increased androgen synthesis in utero causes androgenization of the 46,XX fetus in the first trimester. Ambiguous genitalia are seen at birth, with varying degrees of clitoral enlargement and labial fusion. Excess androgen production causes gonadotropin-independent precocious puberty in males with 21-OHD.
The salt-wasting form of 21-OHD results from severe combined glucocorticoid and mineralocorticoid deficiency. A salt-wasting crisis usually manifests between 5 and 21 days of life and is a potentially life-threatening event that requires urgent fluid resuscitation and steroid treatment. Thus, a diagnosis of 21-OHD should be considered in any baby with atypical genitalia with bilateral nonpalpable gonads. Males (46,XY) with 21-OHD have no genital abnormalities at birth but are equally susceptible to adrenal insufficiency and salt-losing crises.
Females with the classic simple virilizing form of 21-OHD also present with genital ambiguity. They have impaired cortisol biosynthesis but do not develop salt loss. Patients with nonclassic 21-OHD produce normal amounts of cortisol and aldosterone but at the expense of producing excess androgens. Hirsutism (60%), oligomenorrhea (50%), and acne (30%) are the most common presenting features. This is one of the most common recessive disorders in humans, with an incidence as high as 1 in 100 to 500 in many populations and 1 in 27 in Ashkenazi Jews of Eastern European origin.
Biochemical features of acute salt-wasting 21-OHD are hyponatremia, hyperkalemia, hypoglycemia, inappropriately low cortisol and aldosterone, and elevated 17-hydroxyprogesterone, ACTH, and plasma renin activity. Presymptomatic diagnosis of classic 21-OHD is now made by neonatal screening tests for increased 17-hydroxyprogesterone in many centers. In most cases, 17-hydroxyprogesterone is markedly increased. In adults, ACTH stimulation (0.25 mg of cosyntropin IV) with assays for 17-hydroxyprogesterone at 0 and 30 min can be useful for detecting nonclassic 21-OHD and heterozygotes (Chap. 8).
TREATMENT Congenital Adrenal Hyperplasia
Acute salt-wasting crises require fluid resuscitation, IV hydrocortisone, and correction of hypoglycemia. Once the patient is stabilized, glucocorticoids must be given to correct the cortisol insufficiency and suppress ACTH stimulation, thereby preventing further virilization, rapid skeletal maturation, and the development of polycystic ovaries. Typically, hydrocortisone (10–15 mg/m2 per day in three divided doses) is used in childhood with a goal of partially suppressing 17-hydroxyprogesterone (100 to <1000 ng/dL). The aim of treatment is to use the lowest glucocorticoid dose that adequately suppresses adrenal androgen production without causing signs of glucocorticoid excess such as impaired growth and obesity. Salt-wasting conditions are treated with mineralocorticoid replacement. Infants usually need salt supplements up to the first year of life. Plasma renin activity and electrolytes are used to monitor mineralocorticoid replacement. Some patients with simple virilizing 21-OHD also benefit from mineralocorticoid supplements. Parents and patients should be educated about the need for increased doses of steroids during sickness, and patients should carry medic alert systems.
Steroid treatment for older adolescents and adults varies depending on lifestyle, age, and factors such as a desire to optimize fertility. Hydrocortisone remains a useful approach, but treatment with prednisolone at night may provide more complete ACTH suppression. Steroid doses should be adjusted to individual requirements because overtreatment can result in iatrogenic Cushing’s-like features, including weight gain, insulin resistance, hypertension, and osteopenia. Because it is long acting, dexamethasone given at night is useful for ACTH suppression but is often associated with more side effects, making hydrocortisone or prednisolone preferable for most patients. Androstenedione and testosterone may be useful measurements of long-term control, with less fluctuation than 17-hydroxyprogesterone. Mineralocorticoid requirements often decrease in adulthood, and doses should be reassessed and reduced to avoid hypertension in adults. In very severe cases, adrenalectomy has been advocated but incurs the risks of surgery and total adrenal insufficiency.
Girls with significant genital androgenization due to classic 21-OHD usually undergo vaginal reconstruction and sometimes clitoral reduction (maintaining the glans and nerve supply), but the optimal timing of these procedures is debated, as is the need for the individual to be able to consent. There is a higher threshold for undertaking clitoral surgery in some centers because long-term sensation and ability to achieve orgasm can be affected, but the long-term results of newer techniques are not yet known. Full information about all options should be provided. If surgery is performed in infancy, surgical revision or regular vaginal dilatation may be needed in adolescence or adulthood, and long-term psychological support and psychosexual counseling may be appropriate. Women with 21-OHD frequently develop polycystic ovaries and have reduced fertility, especially when control is poor. Fecundity is achieved in 60–90% of women with good metabolic control, but ovulation induction (or even adrenalectomy) may be required. Dexamethasone should be avoided in pregnancy. Men with poorly controlled 21-OHD may develop testicular adrenal rests and are at risk for reduced fertility. Prenatal treatment of 21-OHD by the administration of dexamethasone to mothers is still under evaluation. However, pending methods to diagnose the disorder early in pregnancy, both affected and nonaffected fetuses will be exposed because treatment is started ideally before 6 to 7 weeks. The long-term effects of prenatal dexamethasone exposure on fetal development are still under evaluation, and current guidelines recommend full informed consent before treatment, ideally in a protocol that allows long-term follow-up of all children treated. Newer techniques such as cell-free fetal DNA testing may potentially reduce treatment of nonaffected fetuses.
The treatment of other forms of CAH includes mineralocorticoid and glucocorticoid replacement for salt-losing conditions (e.g., StAR, CYP11A1, HSD3β2), suppression of ACTH drive with glucocorticoids in disorders associated with hypertension (e.g., CYP17, CYP11B1), and appropriate sex hormone replacement in adolescence and adulthood, when necessary.
Increased androgen synthesis can also occur in CAH due to defects in POR, 11β-hydroxylase (CYP11B1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and with mutations in the genes encoding aromatase (CYP19) and the glucocorticoid receptor. Increased androgen exposure in utero can occur with maternal virilizing tumors and with ingestion of androgenic compounds.
OTHER DISORDERS AFFECTING 46,XX FEMALES
Congenital absence of the vagina occurs in association with müllerian agenesis or hypoplasia as part of the Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome (rarely caused by WNT4 mutations). This diagnosis should be considered in otherwise phenotypically normal females with primary amenorrhea. Associated features include renal (agenesis) and cervical spinal abnormalities.
The approach to a child or adolescent with ambiguous genitalia or another DSD requires cultural sensitivity, as the concepts of sex and gender vary widely. Rare genetic DSDs can occur more frequently in specific populations (e.g., 5α-reductase type 2 in the Dominican Republic). Different forms of CAH also show ethnic and geographic variability. In many countries, appropriate biochemical tests may not be readily available, and access to appropriate forms of treatment and support may be limited.